Type 2 diabetes mellitus is a multifaceted and heterogeneous metabolic syndrome, which accounts for 90-95% of all diabetes. This disorder is rapidly emerging as a global health care problem that threatens to reach pandemic levels by 2030; the number of people with diabetes worldwide is expected to rise from 171 million in 2000 to 366 million by 2030. This increase is expected to be most noticeable in developing countries, where the number of people with diabetes is expected to grow from 84 million to 228 million.
A key component of the pathophysiology of Type 2 diabetes mellitus involves an impaired pancreatic β-cell function which eventually contributes to decreased insulin secretion in response to elevated plasma glucose. An early defect in Type 2 diabetes mellitus is insulin resistance which is a state of reduced responsiveness to circulating concentrations of insulin and is often present years before the onset of hyperglycemia and the clinical diagnosis of diabetes. The β-cell compensates for increasing insulin resistance by increasing insulin secretion eventually resulting in reduced β-cell mass. Consequently, blood glucose levels stay at abnormally high levels, which in the long run leads to severe health problems in these patients including, obesity, hypertension and dyslipidemia. Uncontrolled hyperglycemia can further, lead to complications such as nephropathy, neuropathy, retinopathy and premature atherosclerosis.
Glucose-dependent insulin secretion is mainly promoted by incretins, predominantly glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1) (7-36). These gut peptides are released from the gastrointestinal tract in response to nutrition ingestion and promote nutrient assimilation via potentiation of glucose dependent insulin secretion. Based on its physiological profile, the actions of GLP-1 (7-36) are useful for lowering blood glucose in subjects with Type 2 diabetes mellitus and thus have strong potential as chronic therapies for diabetes. Studies in which Type 2 diabetic patients have been infused with GLP-1 have demonstrated efficacy in normalizing both fasted and post-prandial glycemia. However, GLP-1 (7-36) has been shown to have a short half-life in vivo (about 1.5 min) as it undergoes rapid amino terminal (His-Ala) degradation by dipeptidyl peptidase (DPP-IV). DPP-IV is a member of the s9b family of serine peptidases. Dipeptidyl peptidase IV (DPP-IV), also called adenosine deaminase binding protein (ADAbp) or CD26, is a 220-kD homodimeric, Type 2 transmembrane glycoprotein, widely expressed on the surface of a variety of epithelial, endothelial, and lymphoid cell types. DPP-IV regulates various physiological processes by cleaving Xaa-Pro dipeptides from the N-terminus of regulatory peptides, including many chemokines, neuropeptides, and peptide hormones.
GLP-1 (7-36) is degraded by DPP-IV efficiently to GLP-1 (9-36), which has been speculated to act as a physiological antagonist to GLP-1 (7-36) and totally reduces the activity of GLP-1 (7-36). The short half-life of GLP-1 in the circulation is a major obstacle to its use as a therapeutic agent. To circumvent this drawback of GLP-1, DPP-IV inhibition represents a useful strategy for prolonging GLP-1 action leading to sustained lowering of blood glucose. Clinical evidence shows that specific DPP-IV inhibitors lower blood glucose levels in Type 2 Diabetics. Advantageously, since the incretins are produced by the body only when food is consumed and their action, is glucose dependent, DPP-IV inhibition is not expected to increase the level of insulin at inappropriate times, such as between meals, which can lead to hypoglycemic events. Inhibition of DPP-IV is therefore expected to increase insulin without increasing the risk of hypoglycemia, which is a dangerous side effect associated with the use of other insulin secretagogues. The compounds shown below are the DPP-IV inhibitors which have either reached advanced stages of human clinical trials or are either awaiting regulatory approval: Merck's “Sitagliptin” with Formula A is the first DPP-IV inhibitor which has been launched under the name “Januvia”, (Expert Opinion, 2007, 7, 557; Current Topics in Medicinal Chemistry, 2007, 533), Formula B represents Novartis' “Vildagliptin”, Formula C represents Bristol Myers Squibb's “Saxagliptin”, Formula D represents Syrrx's “Alogliptin” and Formula E represents Abbott's “ABT-279”.

A large number of DPP-IV inhibitors have been described in the art. For example, PCT publications WO-199819998; WO-2000034241, WO-2006127530, U.S. Pat. No. 6,110,949, U.S. Pat. No. 6,011,155, U.S. Pat. No. 7,169,806 and Japanese publication JP-2005139107 disclose cyanopyrrolidines as DPP-IV inhibitors. PCT publication WO-2004161514 discloses cyanofluoropyrrolidiries having DPP-IV inhibitory activity. US publications US 20006110949, US 20006107317 and PCT publication WO 199961431 disclose cyanothiazolidines as DPP-IV inhibitors. Aminopiperidine derivatives have been disclosed in, for example, PCT publications WO-2006058064, WO-2006039325, WO-2006058064. Others are pyrrolidine; thiazolidine, piperadine, or pyridine derivatives (see for example. WO-2006116157, WO-2005120494, WO-03084940, WO-2006062063, WO-2005042488). Still others are xanthine and purine derivatives (see for example PCT publications WO-2004018467, WO-2004018469).
β-amino acid based DPP-IV inhibitors have been disclosed in PCT publications, for example, WO-2004043940, WO-2005044195, WO-2006009886, WO-2006023750, WO-2006039325, WO-2003004498, WO-2005116029, WO-2005113510, WO-2006097175, WO-2005120494, WO-2005121131, WO-2005123685, WO-2005040095 WO-2007063928, WO-2007054577, WO-2007053819, WO-2006081151, WO-2004085378 and US patents such as U.S. Pat. No. 7,259,160, U.S. Pat. No. 7,101,871 and U.S. Pat. No. 7,208,498.
The present invention is directed to a class of β-amino acid based DPP-IV inhibitors using novel heterocycles, structurally unrelated to any DPP-IV inhibitors known so far.
Although a number of DPP-IV inhibitors have been described in the art, nonetheless, a need still exists for new DPP-IV inhibitors that have better half life, advantageous potency, stability, selectivity, less toxicity and/or better pharmacodynamics properties. There is a need for DPP-IV inhibitors that can increase the amount of circulating GLP-1 over prolonged period of time, thus leading to better control of diabetes related complications. In this regard, a novel class of DPP-IV inhibitors is provided herein.